The present invention relates to a method for enhancing innate immunity defense mechanisms of vertebrate animals including humans. In accordance with the present invention, innate immunity defenses are enhanced by the administration of plant-derived immunomodulators. These plant-derived immunomodulators may be plant extracts containing steroid-like glycoalkaloids or plant-derived glycoalkaloids. The administration of these immunomodulators significantly augments the antimicrobial activities of the innate immune system. Preferred plant-derived glycoalkaloids include solanine and chaconine.
The publications and other materials used herein to illuminate the background of the invention and in particular cases, to provide additional details respecting the practice, are incorporated by reference, and for convenience are numerically referenced in the following text and respectively grouped in the appended bibliography.
Over the past 50 years, chemical antibiotics have provided clinicians with effective therapies for the prevention, treatment, cure, plus the elimination of horizontal or vertical transmission, of many species of microorganisms capable of causing disease. These successes, however, have led to a high degree of complacency concerning the inevitable threat of acquired bacterial drug resistance. Over the past decade alone, both the frequency and spectrum of multiresistant species of pathogenic bacteria has dramatically increased (1-4). Unfortunately, few new antimicrobial drugs are reported to be under active development (3, 4). Assuming this trend continues, a major clinical problem that we will certainly face early in the 21st century, will be increased numbers of untreatable bacterial infections. Even today, there are species of Streptococcus, Staphylococcus, Pseudomonas, Enterococcus, and Mycobacterium which have developed resistance to all currently available antibiotic therapies (5-8).
It is highly unlikely that specific vaccines for the many pathogenic microorganisms capable of causing disease can be developed rapidly enough to replace our present dependence on antibiotics. In spite of their exceptional effectiveness in the prophylactic treatment against diseases like tetanus, diphtheria, whooping cough, polio, and smallpox, the number of available vaccines is extremely small in comparison to the vast array of different species and strains of bacteria that can cause infectious diseases. Consequently, new strategies need to be pursued to meet the upcoming challenges that are being caused by the emergence of multidrug resistance in bacteria.
Host protection against diseases caused by infectious agents is provided by the immune system, a collection of molecular and cellular mechanisms and processes which function synergistically to either rid the host of the offending agents or control their proliferation (9-16). The innate defense mechanisms of the immune system get involved early postinfection, and their function is to control the extent of infection in an agent nonspecific manner. The generation of acquired or adaptive immunity, with its antigen specificity and high degree of efficiency takes a period of time to develop. Individuals can vary greatly in the efficiency of their innate immune defenses. These differences can spell the difference between an infection which resolves prior to development of overt disease, and an infection which progresses to full-blown disease prior to the mobilization of the acquired immune defense mechanism.
Herbal drugs are broadly represented in the Pharmacopeiae of many countries, including the USA. (23). Currently, 50 drugs discovered from plants are produced by domestic pharmaceutical companies (24). These phytomedicinals play important roles in treating disorders of the digestive, respiratory, cardiovascular, nervous, endocrine, and other organ systems (24, 25). The immune system is also responsive to the therapeutic influences of plant derived compounds. Among these are triterpeniod saponin glycosides from Ginseng, sterols from Eleuthero, high molecular weight polysaccharides (heteroxylan, arabinogalactan) and low molecular weight derivatives (chicoric acid) from Echinacea (25). These substances have no direct bactericidal or bacteriostatic properties (25, 26); rather, their beneficial effects on the immune system are brought about by their ability to increase innate immune defense mechanisms, and in particular, stimulation of phagocytosis, promotion of lymphocite activity, and increased cytokine (TNF-alpha; IFN-gamma) production (25-27). These responses allow the neutralization of some viruses and destruction of bacteria (27, 28).
Modern Chinese medicine utilizes the antimicrobial and antiviral properties of some plants. A polysaccharide complex, lentinan (a derivative of the Shiitake mushroom (Lentinus edodes), came into current clinical use from traditional ancient medicine because of its ability to strengthen the immune system (29).
Sprouts and foliage of Solanum species, including potatoes (Solanum tuberosum L.), and tomatoes (Lycopersicum esculentum), are sources of steroid-like glycoalkaloids which contain a steroid-like aglycon bound to an oligosaccharide moiety (20). There are numerous publications concerning the toxicology of glycoalkaloids in potatoes and tomatoes (18, 19, 30-37). At high concentrations, the major glycoalkaloids of potatoes (solanine and chaconine) and some minor ones can cause poisoning (18, 34, 36). Factors such as environmental or geographic variations, exposure to light (green potatoes), or mechanical damage (harvesting) may result in a critical elevation of glycoalkaloid concentrations in tubers (38, 39). Toxic doses of glycoalkaloids (over 5 mg/kg/body weight) might have disruptive effects on membranes in the gastrointestinal tract and elsewhere. These effects are presumably due to saponine-like properties and can lead to hemolytic and hemorrhagic damage of organs (40). Taken in high doses, glycoalkaloids also inhibit acetylcholinesterase (41) and increase the activity of ornithine decarboxylate (42), which can cause liver dysfunction. Since green potatoes, sprouts, and potato plants contain potentially dangerous levels of glycoalkaloids, they are not recommended for consumption. However, recent studies conducted among some Bangladeshi communities, which consume potato tops (leaves) as regular food, revealed that moderate quantities of glycoalkaloids (below 4 mg/kg/body weight/day) are unlikely to represent a health hazard to humans (12). There are a few reports indicating that some glycoalkaloids from the Solanaceae family at moderate concentrations show direct antiviral and antifungal activities (43-46). No bactericidal or bacteriostatic effect has been described for potato alkaloids, including aglycons, and for triterpenoid compounds from ginseng (25), which have structural similarities to steroid-like aglycons (47).
It is desired to identify compounds which will enhance innate immune defense mechanisms to aid in the battle against infections and which will prove useful in treating antibiotic resistant microbes.